Multi-reservoir device for controlled drug delivery

ABSTRACT

An implantable device for the controlled release of drug or diagnostic molecules in vivo which includes a substrate formed of a metal or a polyethylene, a plurality of discrete reservoirs provided in spaced positions in the substrate, and a release system disposed in the at least two reservoirs, wherein the release system comprises drug or diagnostic molecules combined with a release-controlling polymer matrix, wherein the kinetics of release of the drug or diagnostic molecules is controlled by disintegration of the polymeric matrix. The substrate and reservoirs therein may be made by a manufacturing technique which comprises compression molding, thermoforming, casting, laser cutting, etching, or a combination thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation of U.S. application Ser. No. 10/886,405, filedJul. 7, 2004, which is a divisional of U.S. application Ser. No.09/727,858, filed Dec. 1, 2000, now U.S. Pat. No. 6,808,522. applicationSer. No. 09/727,858 claims benefit of U.S. Provisional application Ser.No. 60/170,218, filed Dec. 10, 1999. The disclosure of U.S. applicationSer. No. 10/886,405 is incorporated herein by reference in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under NIH-R24-AI47739awarded by the National Institutes of Health. The government has certainrights in the invention.

BACKGROUND OF THE INVENTION

This invention relates to miniaturized drug delivery devices and moreparticularly, to controlled time and rate release multi-welled drugdelivery devices.

The efficacy of many drugs is directly related to the way in which theyare administered. A wide variety of methods for controlled release havebeen developed, including pumps, patches, tablets, and implants.However, all of these methods have unique disadvantages when consideringthe treatment of a chronic condition. A major disadvantage of bothexternal and internal micropumps is that they depend on the reliableoperation of moving parts. Failure of the pump due to breakage, leakage,or clogging may be catastrophic for the individual. Patches are usefulonly for certain chemicals that may be absorbed through the skin.Tablets are widely used but can achieve release for only a limitedamount of time before they pass through the digestive system. Manypolymeric materials proposed to be used for pulsatile release of achemical are responsive to changes in pH or temperature (Lee, et al., J.Appl. Polym. Sci. 62:301-11 (1996)), the application of ultrasound(Kost, et al., Proc. Nat. Acad. Sci., USA, 86:7663-66 (1989); Levy, etal., J. Clin. Invest., 83:2074-78 (1989)), changes in enzymes, orchanges in electric (Kwon, et al., Nature, 354:291-93 (1991)) ormagnetic (Kost, et al., J. Biomed. Mater. Res., 21-1367-73 (1987))fields. These polymeric systems are limited to the release of only oneor a few chemicals, and may need to be tailored to the specificcondition which they are to treat (glucose-sensitive insulin releasesystems for the treatment of diabetes, for example (Kitano, et al., J.Control Release, 19:162-70 (1992))). Additionally, the stimuli sourcemay be large, expensive, or too complex for frequent use. Moreover,fabrication procedures for implants such as microspheres are usuallycomplex, and the solvents or heat used during fabrication can adverselyaffect the stability of the drugs contained in the microspheres.

U.S. Pat. No. 5,797,898 and No. 6,123,861, to Santini, et al., describeactive and passive microchips for drug delivery. However, thefabrication methods described therein are primarily based on standardmicroelectronics processing techniques. It would be advantageous toprovide additional, preferably simple and inexpensive, methods ofmanufacturing such microchip devices. It would also be advantageous todevelop new methods of triggering and controlling release of themolecules.

PCT WO 99/03684 discloses a process of making a device having a surfacemicrostructure of wells or channels using a low cost process of screenprinting a curable or polymerizable material onto a plastic substrateand then curing or polymerizing the material. The device can containhundreds of wells and be used as a microtitre plate array, holdingreagents of interest, but it is not designed to provide any sort ofcontrolled release or delivery function.

It is therefore an object of the present invention to provide a varietyof techniques for the manufacture, particularly the low costmanufacture, of multi-welled microchip devices for the controlledrelease of drugs and other molecules.

It is another object of the present invention to provide a device thatallows delivery of drugs or other molecules in either a pulsatile orcontinuous manner, using a variety of materials of construction andmethods for triggering and controlling release of the molecules.

SUMMARY OF THE INVENTION

Methods are provided for manufacturing microchip devices for the storageand controlled release of molecules, such as drugs. Methods includecompression molding, injection molding, thermoforming, casting, andcombinations of these techniques, alone or in combination withmicrofabrication techniques. The methods are adapted to make eitheractive or passive release devices from materials such as polymers,ceramics, and metals. In a preferred embodiment, polymeric devices aremade by (1) filling a die with a polymer powder; (2) compressing thepowder to form a partially or completely dense polymer preform; (3)thermal compression molding the preform in a mold to form a substrate,wherein the mold has a plurality of protrusions which form reservoirs inthe substrate; and (4) filling the reservoirs with a release systemcomprising the molecules to be released. Alternatively, ceramic devicesare formed from a ceramic powder or a slurry thereof which is cast in amold to form the substrate, again wherein the mold has a plurality ofprotrusions which form reservoirs in the substrate.

Each filled reservoir optionally can include reservoir caps that controlrelease. In devices of any substrate material, methods of formingreservoir caps can utilize capillary action depending upon the selectionof appropriate reservoir dimensions.

These fabrication methods preferably further include exposing (i.e.opening) the ends of the reservoirs after molding or casting, by cuttingthe substrate, planarizing the surface of the substrate, or acombination of these techniques.

The release system may be formed solely of the molecules to be releasedin pure form or the molecules may be combined with a release-controllingcomponent, such as a polymeric matrix, which affects the release rateand time through degradation, dissolution, swelling, or disintegrationof the component. The release system also may include a material thatdoes not undergo such processes, but affects the molecule release ratevia diffusion of the molecules through the material. In one embodimentof active release systems, the reservoirs are provided with a cap thatcovers the reservoir and responds directly to an applied externalstimulus (e.g., an applied voltage or potential), or to a change in thelocal environment of the device or reservoir, which is brought about bythe application of the external stimulus (e.g., local pH change orgeneration of an electric field due to the application of a voltage orpotential to electrodes in or near the reservoir). In a preferredembodiment, active release devices are provided with electrodespositioned in, near, or partially covering the reservoirs, such thatupon application of an electric potential or current across theelectrodes, the release system (1) degrades due to local pH changes or(2) exchanges ions in solution with an ionically bound active substance,thereby releasing the molecules from the release system. For example,the release system can be a biodegradable matrix. In another embodiment,the electrodes drive charged molecules from the release system uponapplication of an electric current across the electrodes.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a schematic illustrating one embodiment of a passive deliverydevice having reservoir caps and reservoirs filled with a releasesystem.

FIG. 2 is a schematic illustrating one embodiment of a passive deliverydevice having no reservoir caps and reservoirs filled with a releasesystem.

FIG. 3 is a schematic illustrating one embodiment of an active deliverydevice having electrically responsive reservoir caps and reservoirsfilled with a release system.

FIGS. 4 a-f illustrate a preferred method of molding a partially dense(4 d) and a completely dense (4 f) polymer preform.

FIG. 5 illustrates one embodiment of a molding step for formingreservoirs in a polymeric device.

FIGS. 6 a-c illustrate one embodiment of a polishing step for exposingthe reservoir ends of a substrate having reservoirs formed on one side.

FIGS. 7 a-b illustrate one embodiment of a method for forming reservoircaps in the substrate via microinjection.

FIGS. 8 a-b illustrate one embodiment of a method for forming releasesystems in the substrate via microinjection.

FIGS. 9 a-f illustrate several embodiments of methods for sealing thereservoirs of the device.

FIG. 10 illustrates one embodiment of a method for forming a reservoircap in the substrate using capillary pressure.

FIG. 11 is a schematic illustrating one embodiment of an active deliverydevice having electrodes on reservoir sidewalls.

FIG. 12 is a top view (12 a) and a cross-sectional side view (12 b) ofone embodiment of an active device having electrodes on reservoirsidewalls.

FIGS. 13 a-c are cross-sectional side views of one embodiment of anactive device having electrodes on side walls of a reservoir containingpolymer/active agent matrix (13 a) for a polymer that degrades uponapplication of an electrical current through the electrodes (13 b) andfor a polymer that undergoes ion exchange upon application of theelectrical current (13 c).

DETAILED DESCRIPTION OF THE INVENTION

Microchip devices are provided which can accurately deliver precisequantities of molecules at defined rates and times according to theneeds of the patient or experimental system. As used herein, a“microchip” is defined as a miniaturized device fabricated using formingmethods such as compression molding, injection molding, thermoforming,or other methods described in, for example, Tadmor & Gogos, Principlesof Polymer Processing, (John Wiley & Sons, New York 1979),microinjection, microcontact printing, standard microelectronicsprocessing methods such as photolithography, etching, evaporation, andsputtering as described, for example, in Wolf & Tauber, SiliconProcessing for the VLSI Era, Volume I-Process Technolog (Lattice Press,Sunset Beach, Calif. 1986); Jaeger, Introduction to MicroelectronicFabrication, Volume V in The Modular Series on Solid State Devices(Addison-Wesley, Reading, Mass. 1988); and Campbell, The Science andEngineering of Microelectronic Fabrication (Oxford University Press, NewYork 1996); microfabrication methods described, for example, in Madou,Fundamentals of Microfabrication (CRC Press, 1997); and combinations ofthese methods. The microchips provide control over the rate at which themolecules are released, as well as the time at which release starts.

The fabrication methods described herein may be used to fabricatedevices having primary dimensions (length of a side for square orrectangular devices, or diameter for round devices) that are typically afew centimeters, and preferably a few millimeters, or smaller. Devicedimensions may vary depending on the application. The number and volumeof the reservoirs varies with the device dimensions. Devices for in vivoapplications are small enough to be implanted, injected, orallyadministered, or attached to various mucous membranes.

Release of molecules can be controlled actively, passively, or by acombination thereof. Passive devices do not require the application of astimuli source to effect these changes. Representative methods ofrelease (i.e. triggering mechanisms) for passive devices includedisintegration of a reservoir cap, or diffusion from a release systemcontaining the pure molecules to be released or a mixture of themolecules and an excipient material that affects the release rate and/ortime.

As used herein, unless explicitly indicated otherwise, the terms“disintegrate” or “disintegration” in reference to reservoir caps orrelease system matrix refer to the loss of structural integrity by anymechanism, including, but not limited to, physical fracture, rupture, ordeformation, chemical or enzymatic degradation, and dissolution. Thisincludes rupture of the reservoir cap resulting from swelling of thereservoir cap, the release system, or both.

As used herein, the term “release system” includes the molecules intheir pure form (solid, liquid, or gel), as well as the molecules incombination with other materials that affect the rate and/or time ofrelease of the molecules. These other materials can be, for example, amatrix formed of a biodegradable material or a material that releasesthe incorporated molecules by diffusion or disintegration of the matrix.The “release system” includes mixtures of different forms (e.g., solid,liquid, and/or gel) of the molecules, as well as mixtures of themolecules with various excipient or release-controlling materials thatdisintegrate. A release system also may include a material that does notundergo any of the above processes, but affects the release rate of themolecules as they diffuse through it.

Active devices may be controlled by microprocessors, remote control, orbiosensors. Typical control methods include electric potential and pHcontrol methods. In one embodiment, the application of an electriccurrent or potential causes electrochemical reactions to occur whichtrigger disintegration or another change in the reservoir cap or releasesystem, which can affect both release rate and time. Alternatively, anapplied electric potential or current can change the pH in the localenvironment around a reservoir cap or release system, causing a changein the reservoir cap or release system materials, which can also affectthe release rate and/or time. Examples of release methods include simpledissolution of a reservoir cap due to an electrochemical reaction,electrophoretic delivery of molecules from a release system in areservoir, release of molecules from a reservoir due to ion exchange, orswelling of a release system which causes the reservoir cap to rupture,thereby releasing the molecules from the reservoir.

I. Device Components and Materials

The microchip devices can be described as “passive devices” or “activedevices.” Both types control the rate and time of release of themolecules.

Each microchip device, whether passive or active, includes a substrate,a plurality of reservoirs, and a release system, similar to thatdescribed in U.S. Pat. No. 5,797,898 and No. 6,123,861, to Santini, etal. The reservoirs optionally include reservoir caps, electrodes, orboth.

Substrate

The substrate of the passive and active microchip devices can becomposed of any suitable material that can be fabricated by the methodsdescribed herein. Representative materials include polymers, such aspoly(ethylene), poly(tetrafluoroethylene) and other fluorinatedpolymers, silicones (poly(siloxanes)), and copolymers thereof. Preferredbiodegradable polymers include, for example, poly(anhydrides),polyphosphazenes, pseudo poly(amino acids), and poly(esters) such aspoly(lactide), poly(glycolide), and poly(lactone)s, and copolymersthereof. Other representative materials of construction include metals;semi-conductors, such as silicon; and ceramic materials, such as alumina(aluminum oxide), aluminum nitride, silicon dioxide, silicon nitride,and other various nitrides and oxides.

For in vivo applications, the substrate can be formed or coated with abiocompatible material. For in vitro applications, such as in the fieldof medical diagnostics, the substrate can be constructed ofbiocompatible or non-biocompatible materials.

Reservoir Caps and Release Systems

The reservoirs optionally include reservoir caps. Reservoir caps controlthe release time (and in some cases, release rate) of the molecules bydisintegrating or by affecting diffusion of the molecules through thereservoir cap material. Combinations of both the reservoir caps andrelease systems may be used to achieve the desired release time and ratefor the molecules. FIG. 1 and FIG. 2 illustrate examples of passiverelease devices with reservoir caps (FIG. 1) and without reservoir caps(FIG. 2).

An additional release mechanism for active devices comprises a reservoircap that covers the reservoir of interest and is responsive to adirectly applied stimulus or stimuli (e.g., an applied voltage orpotential), or to a change in the local environment of the device orreservoir, which is brought about by the application of a stimulus(e.g., local pH change or generation of an electric field due to theapplication of a voltage or potential to electrodes in or near thereservoir). Other representative examples of stimuli that can be appliedto induce the response include heat, light (e.g., laser), and magneticfield. FIG. 3 illustrates an embodiment of an active microchip devicehaving reservoirs covered by electrically responsive caps. Other releasemechanisms for active devices include combinations of these stimuliresponsive caps (i.e. active caps) with one or more additional reservoircaps, either active or passive, located underneath the stimuliresponsive cap (e.g., inside the reservoir), which disintegrate afterthe active cap is removed or made permeable.

For embodiments of these devices (both passive and active) in which itis desired to release molecules over a short period of time, reservoircaps or release systems, such as matrices, may be fabricated fromquickly disintegrating materials including, for example,poly(lactide-co-glycolide) copolymers containing a high glycolidecontent, copolymers of poly(lactones) with fast degradation times,certain poly(anhydrides), hydrogels, oligosaccharides, polysaccharides,and rolled metal foils or evaporated, sputtered, or chemical vapordeposited (CVD) thin films (copper films, for example). For applicationsin which a longer use time is desirable, reservoir caps and releasesystems can be fabricated from materials that take longer todisintegrate, Examples include resorbable biological materials such ascholesterol, other lipids and fats, and lipid bilayers, polymers such aspoly(caprolactone) or certain poly(anhydrides), and PLGA copolymers withhigh lactic acid content. For structures in which the molecules to bereleased must diffuse through a release system matrix, reservoir capand/or release system materials may remain intact or disintegrate.

For an active device, reservoir caps can be fabricated fromnon-conducting materials such as the polymers described above orconducting polymers including, for example, polyaniline or polypyrrole.Electrically erodible polymers such as complexes of poly(ethyloxazoline)and poly(methacrylic acid) can be used as a component of a releasesystem (Kwon, et al., Nature, 354:291-93 (1991)), or a reservoir cap.Conducting polymers such as polypyrrole can be mixed with a chemical andused to deliver the chemical via electrophoresis (Miller, Mol. Cryst.Liq. Cryst., 160:297-301 (1988)). Electrodes, circuitry, and conductingreservoir caps which cover the reservoirs can be fabricated frommaterials including, for example, conducting polymers such aspolyaniline or polypyrrole, and metals such as copper, gold, platinum,and silver. Non-conducting, responsive reservoir caps can be made frommaterials such as polymers that are sensitive to pH, electric field, orother environmental conditions.

In some embodiments, the release system responds to the application ofan electric current by either degrading or exchanging ions from solutionwith an active agent that is ionically bound to the polymer. Examples ofmaterials for such release systems include copolymers ofpoly(ethyloxazoline) and poly(methacrylic acid), which have been shownto degrade with an applied current. Other examples include release ofedrophoniumn chloride (a positively charged molecule) through anion-exchange mechanism using a copolymer of2-acrylamido-2-methyl-1-propane sultonic acid and n-butylmethacrylate,or release of dopamine from a composite polymer ofpoly(N-methylpyrrole)-poly(styrene sulfonate), upon application of anapplied current.

Electrodes

In preferred embodiments, the microchip device includes one or moreelectrodes that do not seal reservoirs (as a reservoir cap would).Rather, the electrodes are located inside a reservoir; on a surfaceoutside of a reservoir but near enough to the reservoir to effect achange in its release system (or reservoir cap if present) when theelectrodes are activated (i.e. electric current or potential appliedacross the electrodes); partially covering the reservoir (and reservoircap if present); or a combination thereof.

The electrodes typically are thin films of a conducting metal or dopedsemiconductor.

Molecules to Be Released

A wide variety of molecules can be contained in and released from themicrochip devices. Examples of the molecules include drugs, diagnosticreagents, fragrances, dyes or coloring agents, sweeteners and otherflavoring agents, and compounds used in tissue culture, such as cellulargrowth factors.

The molecules to be released from the microchip device may be in solid,liquid, or gel form, and may be in pure form or mixed with othermaterials that affect the release rate and/or time, by forming a phaseor by providing a diffusional barrier, for example. Molecules can be inthe form of solid mixtures such as amorphous and crystalline mixedpowders, monolithic solid mixtures, and solid interpenetrating networks;in the form of liquid mixtures including, for example, solutions,emulsions, colloidal suspensions, and slurries; and in the form of gelmixtures such as hydrogels.

For in vivo applications, the molecules preferably are a therapeutic,prophylactic, or diagnostic agent. Examples include chemotherapeuticagents, hormones, and painkillers. It is particularly advantageous todeliver bioactive molecules that are efficacious in very smallquantities, such as hormones and steroids.

The quantity of material that can be placed in a microchip is highlydependent on the volume of the microchip device and its geometry.Typical volumes for each square pyramid-shaped reservoir in a substratecan range from a few nanoliters (nl or nL) to a few microliters (μl orμL). Accordingly, larger devices (e.g., 6 cm×6 cm×2.5 cm) can store andrelease several grams of material (e.g., drug), while smaller devices (2mm by 2 mm by 0.3 mm) can store and release as little material asdesired (e.g., sub-nanogram quantities). Similar calculations can beutilized for any substrate material, device geometry, reservoir shapeand size, and molecules to be delivered. For example, a square pyramidreservoir having one 50 μm by 50 μm opening and one 500 μm by 500 μmopening in a 300 μm thick substrate would have a volume of approximately26 nl. If a density of 1 g/cm³is assumed for the release system placedinto the reservoir, then this reservoir will hold approximately 26 μg ofrelease system.

In one embodiment having a polymer substrate, the substrate is circular,about 0.5 inches (1.3 cm) in diameter. The thickness can vary (e.g.,depending on the extent of polishing), and the volume of each reservoirtypically varies with the substrate thickness. In this embodiment, thereservoirs are each conical in shape with an interior angle of about70°. The base of the cone is about 728 μm in diameter, and the height ofthe cone is about 1000 μm. This embodiment has 36 reservoirs, spacedabout 500 μm apart (i.e. about 500 μm between the bases of the conicalopenings), in a 6×6 square array (about 6.8 mm×6.8 mm). For a reservoiropening (small end of cone) of 300 μm in diameter, the substrate is 588μm thick and the reservoir volume is 129 nL. For a reservoir opening of50 μm in diameter, the substrate is 931 μm thick and the reservoirvolume is 138 nL. It is apparent that one can readily change the number,arrangement, and geometry (size and shape) of the reservoirs as needed,for example to suit a particular application or based on manufacturingconsiderations.

II. Methods of Fabricating the Devices

The microchip devices can be made using the methods described below,alone or in combination with the methods described in U.S. Pat. No.5,797,898 and No. 6,123,861, to Santini, et al., which are herebyincorporated by reference.

Fabrication of the Substrate and Reservoirs

In a preferred fabrication method, polymer powder is compression moldedat low temperature (below the T_(g) of the polymer) into a partiallydense preform (see FIG. 4). The preform is subsequently compressionmolded at a temperature between the T_(g) of the polymer ±10° C. and itsdegradation temperature. This compression step involves molding of thepreform on an indenter plate, fabricated out of a metal, ceramic, orother suitable rigid material, in order to create reservoirs in thesubstrate (see FIG. 5). An intermediate compression molding step may beincluded to densify the preform before it is molded on the indenterplate. Alternatively, the preform may be directly molded on the indenterplate, combining the indentation and densification steps. Completedensification of the substrate is desirable for most applications, butresidual porosity may be useful for certain applications in whichdiffusion of molecules into or out of the device is desirable.

Other forming methods, such as injection molding, thermoforming,casting, and other methods known to those skilled in the art can be usedto form a substrate out of a polymer, other materials (e.g., metals), orcombinations thereof.

In another useful fabrication method, a ceramic powder is cast in a moldthat has indenters, whereby a preliminary reservoir-containing substrateis formed via drying of the slurry in the mold. The preliminarysubstrate (green part) is then fired to densify the part.

Reservoirs as initially fabricated may or may not completely penetratethe substrate, depending on the type of indenter plate used forcompression molding, or the configuration of molds used for otherforming methods. For fabrication methods in which the reservoirs asfabricated do not initially penetrate completely through the substrate,the reservoir ends may be exposed by one of several methods, includingcutting of the substrate with a laser, waterjet, or saw; planarizationof the surface through methods such as polishing (see FIG. 6) orchemical or plasma etching; or physical removal of material such as thatobtained in sputtering.

Fabrication of Reservoir Caps for Passive or Active Devices

In a preferred fabrication method, reservoir caps (either conducting ornon-conducting) are formed via microinjection of a solution thatcontains the cap material in a solvent (see FIG. 7), or a suspension orslurry containing the cap material in a non-solvent. Yet another methodof fabricating the reservoir caps or barrier layers is to microinject,in pure liquid form, the cap material. This method is applicable formaterials with low melting points, which can easily be liquefied, and/ormaterials that will remain in liquid or gel form once they have beeninjected into the reservoirs (e.g., where it is desired to have ahydrogel cap on a reservoir).

Formation of the reservoir caps also can be accomplished by inkjetprinting of a solution or slurry of the cap material, or of the capmaterial in pure liquid form, into the reservoirs. Reservoir caps alsocan be formed by spin coating of the cap material on the substrate, orby dipping the substrate (Jackman, et al., Anal. Chem. 70(11):2280-87(1998)) in a liquid volume of the cap material, in its pure form, or ina solution or suspension.

For cap formation via microinjection or inkjet printing, capillarypressure pulls the liquid to the small end of the reservoir. TheYoung-Laplace equation offers a physical explanation of what happens tothe liquid once it is injected into a reservoir. For the configurationshown in FIG. 10, the Young-Laplace equation is:ΔP=γ(2/R ₂−2/R ₁)   EQ. 1where ΔP=the pressure difference (proportional to the stress) betweenthe two sides of the interface, γ=surface tension of the liquid, and R₁and R₂ are the radii of curvature of the droplet in the reservoir (seeFIG. 10). Since the radius of curvature of the liquid is smaller on theside that touches the narrow end of the reservoir, there will be acorresponding pressure or stress that pulls the liquid in thatdirection. Thus, capillary action will drag the liquid to the narrow endof the reservoir and cause the cap to he formed therein.

For passive devices with metallic caps that would dissolve in certainenvironments, a thin foil of the desired metal can be attached to thesubstrate by application of pressure and/or an adhesive. A thin film orlayer of metal may also be formed on the surface via e-beam evaporation,sputtering, chemical vapor deposition, or other deposition methods usedfor the fabrication of thin films or layers.

For some active devices, reservoir caps formed via microinjection orinkjet printing may serve as a support structure upon which outer,stimuli-responsive caps are formed. These inner, supporting caps aresubsequently removed after the outer, responsive caps are formed.Alternatively, for an embodiment in which it is desired to have morethan one cap per reservoir (for example, an outer electricallyresponsive cap and an inner cap that passively controls diffusion), thecap formed via microinjection may remain in place after the outer caphas been formed. Then, when the outer cap is removed, the inner capcontrols the rate of release of the molecules from the reservoir bycontrolling diffusion out of the reservoir. Other embodiments ofmulti-layered or multi-component caps can be made by combining anynumber of disintegratable and non-disintegratable materials.

Fabrication of Release Systems for Passive or Active Devices

Release systems may be formed and deposited in reservoirs via the samemethods described above for the reservoir caps. Namely, microinjectionor inkjet printing of the release system materials in pure liquid form,gel form, solutions, suspensions, emulsions, or slurries. This includescombinations such as liquid excipient+solid release molecules=matrixslurry; solid excipient+liquid release molecules=matrix slurry; solidexcipient+solid release molecules+solvent=solution of matrix materials;solid excipient+solid release molecules+non-solvent=matrix slurry;liquid excipient+liquid release molecules=pure liquid matrix.

Release systems may also be formed and deposited in reservoirs via spincoating of the substrate with the release materials in pure form, as amixture, or as a solution, emulsion, slurry, or suspension, or dippingthe substrate into a liquid volume of the release materials in pure,solution, or suspension form (discontinuous dewetting, described inJackman, et al., Anal. Chem. 70(11):2280-87 (1998)).

Fabrication of Reservoir Caps and Circuitry for Active Devices

In a preferred embodiment, standard photolithography is used to patternthe conducting material (such as a polymer or metal) on the surface ofthe device into the desired configurations in order to form conductingcaps over the reservoirs and circuitry on the surface of the device.E-beam evaporation, sputtering, chemical vapor deposition, metallithography (Chou, et al., Science, 272:85-87 (1996)) or otherdeposition methods may be used to form metal reservoir caps as well ascircuitry on the surface of the device.

Reservoir caps and conducting circuitry on the surface of the device canalso be fabricated using microcontact printing and soft lithographymethods, as described, for example, in Yan, et al., J. Amer. Chem. Soc.,120:6179-80 (1998); Xia, et al., Adv. Maters, 8(12):1015-17 (1996);Gorman, et al., Chem. Mater., 7:52-59 (1995); Xia, et al., Annu. Rev,Mater. Sci., 28:153-84 (1998); and Xia, et al., Angew. Chem. Int. Ed.,37:550-75 (1998).

In a preferred embodiment, active release devices are provided withelectrodes positioned in or near the reservoirs, such that uponapplication of an electric potential or current across or between theelectrodes, the release system, for example one comprising abiodegradable polymeric matrix, (1) degrades due to local pH changes or(2) exchanges ions in solution with an ionically bound active substance,thereby releasing the molecules from the release system. The electrodesare formed by depositing a conducting material (such as a metal) on thesubstrate using standard microfabrication methods such as sputtering,followed by photolithographically patterning photoresist on the metal inthe shape of the electrode, and then etching away the unmasked metal bywet etching. These microfabrication techniques are described, forexample, in U.S. Pat. No. 5,797,898 and No. 6,123,861, to Santini, etal.

FIG. 11 and FIG. 12 illustrate one configuration in which the electrodesare fabricated on one or more surfaces of the reservoir. FIGS. 13 a-cillustrate how such a device can be activated to release the moleculesfrom the release system upon application of an electric potentialbetween or electric current through the electrodes. FIG. 13 b shows apolymer/active agent matrix wherein the polymer degrades uponapplication of the electric current through the electrodes. FIG. 13 cshows a polymer/active agent matrix wherein the polymer undergoes ionexchange upon application of the electric current.

Removal of the Reservoir Cap from Active Devices

For some configurations of active devices, (inner) reservoir caps formedvia microinjection or inkjet printing may serve as supporting structuresupon which (outer) stimuli-responsive, reservoir caps are formed. Theinner reservoir caps optionally can be removed following formation ofthe outer reservoir caps. Alternatively, the inner reservoir caps mayserve both as supporting and release controlling structures, whichremain in the reservoirs after the outer reservoir caps are formed. Theinner reservoir caps can control the release profile of the molecules bydisintegration or diffusion, after the outer reservoir caps have beenremoved or made permeable.

For applications in which it is desired to remove the reservoir cap fromunderneath the conducting caps, this step generally must be completedbefore the reservoir is filled with the molecules to be released.Removal of the cap or barrier layer may be accomplished, for example, byeither an ion beam or reactive ion plasma, or by chemical etching.

Reservoir Filling

The release system containing the molecules for delivery is insertedinto one of the openings of the reservoir by injection (microinjection)or inkjet printing. Each reservoir can contain different moleculesand/or a different dosage. Similarly, the release kinetics of themolecules in each reservoir can be varied by the choice of reservoir capconfiguration and materials and release system composition. In addition,the mixing or layering of release system and cap materials in eachreservoir can be used to tailor the release kinetics to the needs of aparticular application.

The distribution over the microchip of reservoirs filled with therelease system containing the molecules to be delivered can varydepending on the medical needs of the patient or other requirements ofthe system. For applications in drug delivery, for example, the drugs ineach of the rows can differ from each other. Also, the release system ormaterials comprising the release system can differ within each row torelease the drug at different rates and times from different reservoirs.The dosages can also vary within each row. Differences in reservoirloading can be achieved by injection or inkjet printing of differentamounts of material directly into each reservoir. Although injection andinkjet printing are the preferred methods of filling reservoirs, it isunderstood that each reservoir can be filled individually by capillaryaction, by pulling or pushing the material into the reservoir using avacuum or other pressure gradient, by melting the material into thereservoir, by centrifugation and related processes, by manually packingsolids into the reservoir, by spin coating, or by any combination ofthese or similar reservoir-filling techniques. FIG. 8 illustratesfilling of reservoirs with release system via microinjection.

Device Packaging Control Circuit and Power Source

After the molecules to be released have been inserted into thereservoirs, the backside of the device (side with open ends ofreservoirs into which the release systems and molecules have beenplaced) is sealed with a material or combination of materials that areimpervious to the surrounding medium. Examples of these materialsinclude waterproof, thermally- or UV-curable epoxies; spray adhesives;glass microscope slides and cover glasses; silicon; ceramics; rubbers;and polymeric materials such as poly(tetrafluoroethylene) orpoly(caprolactone). FIG. 9 illustrates sealing a microchip using amicroslide glass cover secured with an adhesive spray, for in vitroapplications. Other examples of sealing methods also are shown in FIG.9. For embodiments in which the entire device is desired to bebiodegradable, the sealant material must have a degradation time that isgreater than the longest release time of the molecules in the device, inorder to prevent dose dumping or leaking of the molecules through thedegraded sealant material.

Control over the release rate and time of molecules from the passivedevices is based upon the design and fabrication of the device, forexample the reservoir cap materials and thicknesses, release systemcompositions, or size of reservoir openings. Thus no control circuitryor power source is necessary for the passive devices.

Further details on packaging, control circuitry, and power sources forthe active devices are described in U.S. Pat. No. 5,797,898 and No.6,123,861, to Santini, et al.

In one embodiment, the microchip device is surface modified (e.g.,coated) to provide a desired functionality, such as to enhancebiocompatability or bioadhesion using techniques known in the art. It isgenerally preferred that the release mechanism (i.e., release from thereservoirs) of the microchip device not be altered by the surfacemodification.

III. Applications for Using the Microchip Devices

Passive and active devices have numerous in vivo, in vitro, andcommercial diagnostic applications. The microchips are capable ofdelivering precisely metered quantities of molecules and thus are usefulfor in vitro applications, such as analytical chemistry and medicaldiagnostics, as well as biological applications such as the delivery offactors (e.g., growth factors and regulating factors) to cell cultures.In other applications, the devices are used to control release offragrances, dyes, reagents, or other useful chemicals.

In one embodiment, the microchip devices can be used in vivo for thedelivery of drugs to humans and animals. The microchips are especiallyuseful for drug therapies in which it is desired to control the exactamount, rate, and/or time of delivery of the drug. Due to the small sizeof these devices, preferred drug delivery applications include thedelivery of potent compounds such as hormones, steroids, chemotherapymedications, gene therapy compounds and vectors, and some strongpainkillers, as the amount of the molecules that may be stored in thedevices is relatively small. The microchips can be implanted viasurgical procedures or injection, or swallowed, and can deliver manydifferent drugs, at varying rates and varying times.

The present invention will be further understood with reference to thefollowing non-limiting examples.

EXAMPLE 1 Fabrication of Polymeric Microchip Device Having CholesterolReservoir Caps

The following procedure was used to produce a polymeric microchip devicehaving cholesterol reservoir caps for passive release.

(1) Weighed 0.4 g of poly(lactic-co-glycolic acid) powder, molecularweight ˜25,000 powder (see FIG. 4 a).

(2) Inserted bottom piston into conical steel die. 1.27 cm (½″) indiameter, filled with polymer powder from step (1), and inserted toppiston into die (see FIG. 4 b).

(3) Put the die with powder into Carver Laboratory Press, model C.Pressed at room temperature for one minute and thirty seconds atapproximately 69×10⁶ Pa (10,000 psi), yielding a cylindrical polymerpreform (see FIG. 4 c).

(4) Removed cylindrical polymer preform from the die (see FIG. 4 d).

(5) Placed cylindrical polymer preform into aluminum die plate (aluminumsheet, approximately 3 mm (or ⅛″) thick, with a hole of approximatelythe same diameter as the polymer preform). Allowed die plate to rest onTeflon sheet, approximately 1.6 mm thick ( 1/16″), and covered top withanother aluminum plate, 3 mm (or ⅛″) thick (see FIG. 4 e).

(6) Placed the assembly from (5) into Carver Laboratory Press, model C,at 104° C. (220° F.). Set temperature of heated platens to about 54° C.(130° F.). As the polymer preform melted, the platens were slowlybrought together. The load pressure remained between 0 and 4448 N (1000pounds-force). The assembly was left in the lab press until the platenscooled to 54° C. (130° F.), approximately one to one and a half hours.

(7) Removed the assembly from the lab press. The assembly was furthercooled by running under cool water (see FIG. 4 f).

(8) Placed aluminum die plate (with densified polymer preform in it) ontop of aluminum indenter plate, containing an array of indenters forforming the reservoirs in the polymeric substrate. Covered the top ofaluminum die plate with another aluminum plate, 3 mm thick (see FIG. 5).

(9) Placed the assembly into Carver Lab Press, Model C, at 54° C. (130°F.). As polymer preform remelted, the platens were brought together andpressure slowly applied until pressure gauge read between 11120 and13344 N (2500 and 3000 pounds-force). Hot pressed the preform in thismanner for 20 minutes, which formed reservoirs in the polymericsubstrate. A hole machined in the side of the indenter plate allowedmonitoring of the temperature close to the polymer preform. A T-typethermocouple connected to an Omega HH21 microprocessor thermometer wasused.

(10) Removed the assembly from Lab Press and allowed it to cool inambient air to approximately 32° C. (90° F.).

( 11) Removed indented polymer preform, i.e. the substrate, fromaluminum indenter and die plates.

(12) Attached the indented polymer preform to suitable mount using anadhesive. Double-sided tape was used to affix the indented polymerpreform to a cylindrical brass block, approximately 3.81 cm (1½″) indiameter and approximately 1.27 to 3.81 cm (½″ to 1½″) tall (see FIG. 6a). Ensured that the indented side of the preform was facing the mount.Alternatively, a multiple-mount polishing fixture similar to thoseavailable commercially may be used to hold the samples during polishing.

(13) Polished the substrate using Buehler Ecomet IV Rotary Polisher,until ends of reservoirs were exposed (see FIG. 6 b and FIG. 6 c).Substrate was checked frequently to monitor the progress of thepolishing. Typical polishing procedure with ranges of polishing timesare shown in Table 1. TABLE 1 Polishing Materials and ProceduresPolishing Polisher Time (range Type of Paper Paper Grit Speed Media inmin:sec) Buehler Carbimet  400 250 rpm water 4:30-6:00 Silicon Carbide 600 250 rpm water 1:00-3:00 Grinding Paper Buehler Microcut  800(P2400) 250 rpm water 0:30-2:00 Silicon Carbide Grinding Paper 1200(P4000) 250 rpm water 0:30-1:30(14) Removed the substrate from the mount. A solvent may be used toloosen the adhesive and aid substrate removal from the mount. Forsubstrates mounted with double sided tape on brass blocks, soaking ofthe substrate in ethanol for 5 to 20 minutes was found to loosen theadhesive.(15) Mixed desired solutions for formation of reservoir caps (e.g.,solutions of 5, 10, 15, and 20 weight % cholesterol in chloroform wereused). Gently mixed the solution with a magnetic stir plate and magneticstirrer bar for at least five minutes. Cholesterol was utilized becauseit is known to be biocompatible, dissolvable, and resorbable in vivo.(16) Filled a Becton-Dickinson 1 mL plastic syringe (item #309602) withdesired cap solution.(17) Attached a World Precision Instruments MicroFil™ Flexible needle(item #MF34G-5) to syringe.(18) Inserted MicroFil™ needle into end of a Unimetrics 10 μL Luer Lockglass syringe (World Precision Instruments item #14392), oppositeplunger.(19) Depressed plunger on 1 mL plastic syringe, filling 10 μL glasssyringe with cap solution.(20) Removed MicroFil™ needle from glass syringe.(21) Placed end of MicroFil™ needle in reservoir end of Hamiltoninstruments 32 gauge needle (item #91032). Depressed plunger on plastic1 mL syringe in order to fill needle reservoir with cap solution, whichminimized formation of air bubbles when needle was attached to glasssyringe.(22) Attached 32 gauge needle to 10 μL glass syringe.(23) Placed 10 μL glass syringe assembly into syringe chamber on WorldPrecision Instruments microinjector (item #UMP-G).(24) Placed the substrate to be injected on glass slide assembly, withone end of reservoirs facing up and the edges of the device resting onthe glass slides. Ensured that ends of reservoirs on opposite side werenot resting on a surface. Tape was used to hold substrate in place onglass slides.(25) Entered desired total injection volume and volume flow rate onWorld Precision Instruments Micro 1™ Microsyringe Pump Controller(typical volumes were between about 20 and 200 nL, at a flow rate of 20nL/sec).(26) Tilted microinjector assembly and aligned needle tip with rows ofreservoirs (see FIG. 7 a).(27) Using fine control knobs, placed needle tip in reservoir into whichcap solution was to be injected.(28) Depressed “Run” button to inject desired volume into reservoir.(29) Using fine control knobs on microinjector, removed needle fromreservoir and moved to next reservoir to be injected.(30) Repeated steps (26) through (29) until all desired reservoirs werefilled with cap solution (see FIG. 7 b).(31) Removed 10 μL glass syringe from microinjector.(32)-(47) Repeated steps (15) through (30) for release systems (pureliquid molecules or mixture of molecules and excipient) (see FIG. 8 aand FIG. 8 b). Here, the release system used was deionized watercontaining approximately 10 mM concentration of sodium flourescein, andapproximately 20% by volume of poly(ethylene glycol), having a molecularweight of 200. Approximately 20 nL of this solution was injected, at aninjection rate of 20 nL/s, into each reservoir from which it was desiredto release the fluorescein. Separate syringes were used for capsolutions and release system solutions to avoid contamination.(48) Sprayed microcover glass (VWR Brand Micro Cover Glass, Square, No.1, 22 mm square×0.13-0.17 mm thick, VWR item #48366-067), with 3M Super77 Spray Adhesive. Waited until adhesive became tacky (see FIG. 9).(49) Using tweezers, placed polymer device on micro cover glass (orother suitable covering material). The injected side of the substratecontacted the cover, leaving the reservoir caps accessible, and therebysealing the microchip device.(50) Allowed the adhesive to dry. The microchip device was then readyfor use (see FIG. 9).

EXAMPLE 2 Fabrication of Polymeric Microchip Device HavingCholesterol/Lecithin Reservoir Caps

The following alternative procedure was used to produce a polymericmicrochip device having cholesterol/lecithin reservoir caps for passiverelease.

(1)-(4) Followed steps (1) through (4) described in Example 1 to form apolymer preform.

(5) Placed cylindrical polymer preform into aluminum die plate (aluminumsheet, approximately 3 mm (or ⅛″) thick, with a hole of approximatelythe same diameter as the polymer preform). Allowed die plate to rest onaluminum plate having conical indenters, and covered top with anotheraluminum plate, 3 mm (or ⅛″) thick.

(6) Placed the assembly from (5) into Carver Laboratory Press, model C,at 54° C. (130° F.). Set temperature of heated platens to 54° C. (130°F.). The load pressure remained at approximately 8896 N (2000pounds-force). The assembly was left in the lab press for approximatelyten minutes. A hole machined in the side of the indenter plate allowedmonitoring of the temperature close to the polymer preform. A T-typethermocouple connected to an Omega HH21 microprocessor thermometer wasused.

(7) Removed the assembly from Lab Press and allowed it to cool inambient air to approximately 32° C. (90° F.).

(8) Removed indented polymer preform, i.e. the substrate, from aluminumindenter and die plates.

(9) Attached indented polymer preforms to suitable mounts using anadhesive. Double-sided tape was used to affix the indented polymerpreforms to cylindrical polymer blocks, approximately 2.54 cm (1″) indiameter and approximately 2.54 cm (1″) tall. Ensured that the indentedsides of the preforms were facing the mount.

(10) Loaded the mounted substrates into a multiple sample holder(Buehler item 60-5160, Controlled Material Removal Accessory) and setdiamond stops to desired thickness of material to be removed (typically1.32 mm or 0.052″). ( 11) Loaded sample holder into Buehler Ecomet IVRotary Polisher, and polished substrates until ends of reservoirs wereexposed/surface of samples became level with diamond stops. Substrateswere checked frequently to monitor the progress of the polishing.Typical polishing procedures with ranges of polishing times are shown inTable 2. TABLE 2 Polishing Materials and Procedures Polishing PolisherTime (range Type of Paper Paper Grit Speed Media in min:sec) BuehlerCarbimet  320 250 rpm water 4:30-6:00 Silicon Carbide  600 250 rpm water1:00-3:00 Grinding Paper Buehler Microcut 1200 (P4000) 250 rpm water0:30-1:30 Silicon Carbide Grinding Paper(12) Followed step (14) described in Example 1 to remove the substratefrom the mount.(13) Mixed desired solutions for formation of reservoir caps (e.g.,solutions of 2 wt. % cholesterol and 3 wt. % lecithin (which is acrystallization inhibitor for cholesterol) in a mixture of chloroformand ethanol). Gently mixed the solution with a magnetic stir plate andmagnetic stirrer bar for at least 5 minutes.(14)-(29) Followed steps (16) through (31) described in Example 1 toform reservoir caps.(30)-(45) Repeated steps (14) through (29) for release systems (pureliquid molecules or mixture of molecules and excipient). In this case,the release system used was deionized water with approximately 13 mMconcentration of sodium fluorescein. Approximately 20 nL of the releasesystem was injected, at an injection rate of 205 nL/sec, into eachreservoir from which it was desired to release fluorescein. Separatesyringes were used for cap solutions and release system solutions toavoid contamination.(46) Mixed Master Bond EP30HTF epoxy according to directions.(47) Using a toothpick, coated one side of rubber o-ring (Greene RubberCompany, item # 2-001 N0674-70 BUNA-N O-RING) with epoxy, and placedo-ring on surface of substrate (side of microchip device oppositereservoir caps). Repeated step for each reservoir filled with releasesystem.(48) Let epoxy dry for at least four hours.(49) Mixed another batch of Master Bond EP30HTF epoxy according todirections, and then coated thin layer of epoxy on backside of microchipdevice over all areas outside of o-rings.(50) Let epoxy dry for at least four hours.(51) Mixed a further batch of Master Bond EP30HTF epoxy according todirections; coated a thin layer of epoxy on top surface of o-rings; andaffixed glass microscope slide to top of o-rings, sealing the microchipdevice.(52) Allowed the epoxy dry for at least 24 (preferably 48) hours. Themicrochip device was then ready for use.

EXAMPLE 3 Fabrication of Polymeric Microchip Device Having PolymericReservoir Caps

The following procedure was used to produce a polymeric microchip devicehaving polyester reservoir caps for passive release.

(1) Weighed desired amount of a polymer powder (see FIG. 4 a). Here, 0.4g of poly(lactic acid) (MW approximately 100,000) was used.

(2) Inserted bottom piston into conical steel die , 1.27 cm (½ inch) indiameter, filled die with polymer powder from step (1), and inserted toppiston into die (see FIG. 4 b).

(3) Placed the die with powder into Carver Laboratory Press, model C.Pressed at room temperature for one minute and thirty seconds atapproximately 69×10⁶ Pa (10,000 psi), yielding a cylindrical polymerpreform (see FIG 4 c).

(4) Removed cylindrical polymer preform from the die (see FIG. 4 d).

(5) Placed polymer preform on aluminum die plate containing an array ofindenters for forming the reservoirs in the polymeric substrate. Analuminum plate 3 mm thick, with a 1.27 cm (½″) diameter hole in it, wasplaced on top of the indenter plate so that the polymer preform wassitting in the hole of the plate. Covered the top of this aluminum platewith another aluminum plate, 3 mm thick (see FIG. 5).

(6) Placed the assembly into Carver Lab Press, Model C, at 182° C. (360°F.). Platens were brought together and pressure slowly applied untilpressure gauge read between 4448 and 8896 N (1000 and 2000pounds-force). Hot pressed the preform in this manner for 15 minutes,which formed reservoirs in the polymeric substrate. A hole machined inthe side of the indenter plate allowed monitoring of the temperatureclose to the polymer preform. A T-type thermocouple connected to anOmega HH21 microprocessor thermometer was used.

(7) Removed the assembly from Lab Press and allowed it to cool inambient air to approximately 32° C. (90° F.).

(8) Removed indented polymer preform, i.e. the substrate, from aluminumindenter and die plates.

(9) Attached indented polymer preforms to suitable mounts using anadhesive. Double-sided tape was used to affix the indented polymerpreforms to cylindrical polymer blocks, approximately 2.54 cm (1″) indiameter and approximately 2.54 cm (1″) tall. Ensured that the indentedsides of the preforms were facing the mount.

(10) Loaded the mounted substrates into a multiple sample holder(Buehler item 60-5160, Controlled Material Removal Accessory) and setdiamond stops to desired thickness of material to be removed (typically1.32 mm or 0.052″).

(11) Loaded sample holder into Buehler Ecomet IV Rotary Polisher, andpolished substrates until ends of reservoirs were exposed/surface ofsamples became level with diamond stops. Substrates were checkedfrequently to monitor the progress of the polishing. Typical polishingprocedure with ranges of polishing times are shown in Table 3. TABLE 3Polishing Materials and Procedures Polishing Polisher Time (range Typeof Paper Paper Grit Speed Media in min:sec) Buehler Carbimet  240 250rpm water 1:00-3:00 Silicon Carbide  600 250 rpm water 1:00-3:00Grinding Paper Buehler Microcut 1200 (P4000) 250 rpm water 0:30-1:30Silicon Carbide Grinding Paper(12) Removed the substrate from the mount. A solvent may be used toloosen the adhesive and aid substrate removal from the mount. Forsubstrates mounted with double sided tape on brass blocks, soaking ofthe substrate in ethanol for 5 to 20 minutes loosened the adhesive.(13) Mixed desired solutions for formation of reservoir caps (e.g.,solutions of 5 to 10 vol. % of poly(L-lactic-co-glycolic acid),molecular weight of approximately 25,000, in dichloromethane). Gentlymixed the solution with a magnetic stir plate and magnetic stirrer barfor at least 5 minutes.(14) Filled a Becton-Dickinson 1 mL plastic syringe (item #309602) withdesired cap solution.(15) Attached a World Precision Instruments MicroFil™ Flexible needle(item #MF34G-5) to syringe.(16) Inserted MicroFil™ needle into end of a Unimetrics 50 μL Luer Lockglass syringe (World Precision Instruments item #15895), oppositeplunger.(17) Depressed plunger on 1 mL plastic syringe, filling 50 μL glasssyringe with cap solution.(18) Removed MicroFil™ needle from glass syringe.(19) Placed end of MicroFil™ needle in reservoir end of Hamiltoninstruments 32 gauge needle (item #91032). Depressed plunger on plastic1 mL syringe in order to fill needle reservoir with cap solution, whichminimized formation of air bubbles when needle was attached to glasssyringe.(20) Attached 32 gauge needle to 50 μL glass syringe.(21) Placed 50 μL glass syringe assembly into syringe chamber on WorldPrecision Instruments microinjector (item #UMP-G).(22) Placed the substrate to be injected on glass slide assembly, withone end of reservoirs facing up and the edges of the device resting onthe glass slides. Ensured that ends of reservoirs on opposite side werenot resting on a surface. Tape was used to hold substrate in place onglass slides.(23) Entered desired total injection volume and volume flow rate onWorld Precision Instruments Micro 1™ Microsyringe Pump Controller(typically multiple injections of 100-200 nL will be done at a flow rateof 205 nL/sec).(24) Tilted microinjector assembly and aligned needle tip with rows ofreservoirs (see FIG. 7 a).(25) Using fine control knobs, placed needle tip in reservoir into whichcap solution was to be injected.(26) Depressed “Run” button to inject desired volume into reservoir.(27) Using fine control knobs on microinjector, removed needle fromreservoir and moved to next reservoir to be injected.(28) Repeated steps (25) through (27) until all desired reservoirs werefilled with cap solution (see FIG. 7 b).(29) Removed 50 μL glass syringe from microinjector.(30)-(45) Repeated steps (13) through (28) for release systems (pureliquid molecules or mixture of molecules and excipient) (see FIG. 8 aand FIG. 8 b). The release system used was deionized water containingapproximately 13 mM concentration of sodium flourescein, and 20 nL ofthis solution was injected, at an injection rate of 205 nL/s, into eachreservoir from which it is desired to release fluorescein. Used separatesyringes for cap solutions and release system solutions to avoidcontamination.(46) Mixed Master Bond EP30HTF epoxy according to directions.(47) Using a toothpick, coated one side of rubber o-ring (Greene RubberCompany, item # 2-001 N0674-70 BUNA-N O-RING) with epoxy, and placedo-ring on surface of substrate (side of microchip device oppositereservoir caps). Repeated step for each reservoir filled with releasesystem.(48) Let epoxy dry for at least four hours.(49) Mixed another batch of Master Bond EP30HTF epoxy according todirections, and then coated thin layer of epoxy on backside of microchipdevice over all areas outside of o-rings.(50) Let epoxy dry for at least four hours.(51) Mixed a farther batch of Master Bond EP30HTF epoxy according todirections, and coated a thin layer of epoxy on top surface of o-rings,and affixed glass microscope slide to top of o-rings, sealing themicrochip device.(52) Let epoxy dry for at least 24 (preferably 48) hours. The microchipdevice was then ready for use.

EXAMPLE 4 Fabrication of Ceramic Microchip Device Having CholesterolReservoir Caps

The following procedure is one that can used to produce ceramicmicrochip devices having cholesterol reservoir caps for passive release.

(1) Weigh out desired amount of ceramic powder or measure a desiredamount of a slurry containing the ceramic.

(2) Compression mold the ceramic powder, or cast the slurry, at roomtemperature with an indenter plate to form partially dense,reservoir-containing substrate.

(3) Densify the substrate of step (2) via sintering at high temperature.

(4)-(6) Polish the substrate as described in steps (12) through (14) ofExample 1. Polishing grits, speeds, and times will vary from those usedfor the polymer devices.

(7)-(23) Form reservoir caps via microinjection of cap solution asdescribed in steps (15) through (31 ) of Example 1.

(24)-(39) Fill reservoirs with release system via microinjection asdescribed in steps (32) through (47) of Example 1.

(40-46) Seal microchip as described in steps (46) through (52) ofExample 2.

EXAMPLE 5 Fabrication of Polymeric Microchip Device for Active Release,Using Microinjection and Photolithography

The following procedure can be used to produce polymeric microchipdevices for active release.

(1)-(31) Follow steps (1) through (31) of Example 1 to form polymericsubstrate having reservoirs and reservoir caps.

(32) Using standard microfabrication techniques, pattern an electricallyerodible polymer, such as a complex of poly(ethyloxazoline) andpoly(methacrylic acid), reservoir cap material over the desired regionsof the substrate, which includes the area over the reservoir openings.This would typically involve:

-   -   (a) spin coating of the polymer and a photoresist;    -   (b) photolithography to expose and develop the photoresist;    -   (c) removal of the polymer from specified regions of the        substrate surface (excluding regions protected by photoresist)        via methods such as chemical, plasma, or ion beam etching;    -   (d) removal of the photoresist from the remaining areas of the        substrate; and    -   (e) optional removal of the inner reservoir cap (underneath the        conducting polymer cap) by etching the backside of the substrate        via chemical, plasma, or ion etching.        (33)-(48) Fill with the reservoirs with the molecules to be        released as described in steps (15) through (30) of Example 1.        (49)-(55) Seal the microchip device as described in steps (46)        through (52) of Example 2.

EXAMPLE 6 Fabrication of Ceramic Microchip Device for Active Release,Using Microinjection and Photolithography

The following procedure is one that can be used to produce ceramicmicrochip devices for active release.

(1)-(6) Follow steps (1) through (6) of Example 4 to form and polish theceramic substrate.

(7)-(22) Fabricate reservoir caps via microinjection as described insteps (32) through (47) of Example 1.

(23) Pattern electrically conducting material to form electricalcircuitry and conducting caps over reservoirs as described in step (32)of Example 5.

(24)-(39) Fill reservoirs with release systems via microinjection asdescribed in steps (32) through (47) of Example 1.

(40)-(46) Seal microchip device as described in steps (46) through (52)of Example 2.

EXAMPLE 7 Fabrication of Polymeric Microchip Device for Active Release,Using Microinjection and Microcontact Printing

The following is another procedure that can be used to produce polymericmicrochip devices for active release.

(1)-(30) Follow steps (1) through (30) of Example 1 to form polymericsubstrate having reservoirs and inner reservoir caps.

(31) Pattern conducting circuitry and outer reservoir caps onto innerreservoir caps using standard microcontact printing methods. See, forexample, Gorman. et al., Chem. Mater., 7:526-529 (1995); Xia et al.,Adv. Mater., 8:1015:1017 (1996); Yan et al., J. Am. Chem. Soc.,120:6179-6180 (1998); Marzolin et al., Thin Solid Films, 315:9-12(1998).

(32) If desired, remove inner reservoir caps from under outer reservoircaps using etching methods, as described in step (32e) of Example 5.

(33)-(48) Fill the reservoirs with the molecules to be released asdescribed in steps (32) through (47) of Example 1.

(49)-(55) Seal the microchip device as described in steps (46) through(52) of Example 2.

EXAMPLE 8 Fabrication of Ceramic Microchip Device for Active ReleaseUsing Microinjection and Microcontact Printing

The following is another procedure that can be used to produce ceramicmicrochip devices for active release.

(1)-(6) Follow steps (1) through (6) of Example 4 to form and polish theceramic substrate.

(7)-(23) Fabricate reservoir caps via microinjection as described insteps ( 15) through (31) of Example 1.

(24) Pattern conducting circuitry and outer reservoir caps onto innerreservoir caps using standard microcontact printing methods.

(25) If desired, remove inner reservoir caps from under outer reservoircaps using etching methods as described in step (32e) of Example 5.

(26)-(41) Fill with the molecules to be released as described in steps(32) through (47) of Example 1.

(42)-(48) Seal the microchip device as described in steps (46) through(52) of Example 21.

Publications cited herein and the material for which they are cited arespecifically incorporated by reference. Nothing herein is to beconstrued as an admission that the invention is not entitled to antedatesuch disclosure by virtue of prior invention.

Modifications and variations of the methods and devices described hereinwill be obvious to those skilled in the art from the foregoing detaileddescription. Such modifications and variations are intended to comewithin the scope of the appended claims.

1. An implantable device for the controlled release of drug ordiagnostic molecules in vivo comprising: a substrate formed of a metalor a polyethylene; a plurality of discrete reservoirs provided in spacedpositions in the substrate; and a release system disposed in the atleast two reservoirs, wherein the release system comprises drug ordiagnostic molecules combined with a release-controlling polymer matrix,wherein the kinetics of release of the drug or diagnostic molecules iscontrolled by disintegration of the polymeric matrix or diffusion of thedrug through the polymer matrix.
 2. The device of claim 1, wherein thesubstrate and reservoirs therein are made by a manufacturing techniquewhich comprises compression molding, thermoforming, casting, lasercutting, etching, or a combination thereof.
 3. The device of claim 1,wherein the substrate is at least partially porous.
 4. The device ofclaim 1, wherein the reservoirs are conical or pyramidal in shape. 5.The device of claim 1, wherein the polymeric matrix material comprises apoly(lactide-co-glycolide), a poly(lactone), or a poly(anhydride). 6.The device of claim 1, wherein the at least two reservoirs individuallycomprise at least two layers of a release system and at least one layerof a degradable or soluble material which does not comprise the one ormore drugs.
 7. The device of claim 1, further comprising at least twodiscrete, reservoir caps covering the at least two reservoirs.
 8. Thedevice of claim 7, wherein the reservoir caps are formed of abioresorbable biological material selected from lipids, fats,poly(lactide-co-glycolide)s, polycaprolactones, and poly(ahnhydrides).9. The device of claim 8, wherein the reservoir caps comprise acholesterol, a lecithin, or a mixture thereof.
 10. The device of claim1, wherein the molecules for release comprise a growth factor.
 11. Thedevice of claim 1, wherein the rate or time of release of the drugmolecules from one of the reservoirs is different from the rate or timeof release of the drug molecules from another of the reservoirs.
 12. Thedevice of claim 1, wherein the reservoirs each have an opening in thesubstrate having a dimension between 50 microns and 300 micron.
 13. Animplantable medical device for the controlled delivery of a drugcomprising: a substrate. an array of discrete reservoirs in thesubstrate; and a release system in the reservoirs comprising drugmolecules for release and a matrix material which comprises a resorbablebiological material selected from the group consisting of fats, lipids,and lipid bilayers, the matrix material disintegrating in vivo torelease the drug molecules, wherein the device is formed of or coatedwith a biocompatible material suitable for implantation into a human oranimal.
 14. The device of claim 13, wherein the matrix materialcomprises a cholesterol, a lethicin, or a combination thereof.
 15. Thedevice of claim 13, wherein the substrate comprises a biodegradablepolymer.
 16. The device of claim 13, further comprising discretereservoir caps covering the release system, wherein release of the drugmolecules is controlled in part by in vivo disintegration orpermeabilization of the reservoir caps.
 17. The device of claim 13,wherein a substrate is formed of a metal or a polyethylene.
 18. Thedevice of claim 13, wherein the substrate and reservoirs therein aremade by a manufacturing technique which comprises compression molding,thermoforming, casting, laser cutting, etching, or a combinationthereof.
 19. The device of claim 13, wherein the substrate is at leastpartially porous.
 20. The device of claim 13, wherein the reservoirs areconical or pyramidal in shape.